Molecular mechanisms of arrhythmia caused by high-fat diet

高脂饮食引起心律失常的分子机制

基本信息

批准号：
10316166
负责人：
John Pearce Morrow
金额：
$ 40万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-01-15 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10316166
关键词：
Arrhythmia CRISPR/Cas technology Calcium Cardiac Cardiac Myocytes Data Diet Electrophysiology (science)Fatty Acids Frequencies Functional disorder Genes Genetic Genetic Models Genetic Transcription Heart High Fat Diet Human Inner mitochondrial membrane Intake Ion Channel Knockout Mice Link Lipids Methods Mitochondria Modeling Molecular Mus NADPH Oxidase Obesity Olive oil preparation Optics Oxidases Oxidative Stress Pathway interactions Risk Rodent Model Sarcoplasmic Reticulum Serum Signal Transduction TLR4 gene Testing Transgenic Mice Ventricular Ventricular Fibrillation Ventricular Tachycardia Wild Type Mouse acetovanillone calcium uniporter diet-induced obesity experimental study heart rhythm human stem cells in vivo inhibitor lipid metabolism mitochondrial dysfunction monounsaturated fat obese patients prevent saturated fat sudden cardiac death

项目摘要

Obese patients have an increased risk of arrhythmias and twice the risk of sudden cardiac death, which is often caused by ventricular tachycardias (VT). Cardiomyocytes from obese patients have increased lipid content, which is thought to contribute to the pathophysiology of arrhythmia. Furthermore, higher levels of serum fatty acids and higher saturated fat intake in the diet predict sudden cardiac death. This suggests that the arrhythmogenic effects of saturated fat can occur without obesity. An unanswered question is: What are the molecular mechanisms causing arrhythmias during obesity and high-fat diet? The most common electrophysiologic abnormalities found in obese patients are increased frequency of ventricular ectopy and prolongation of the QT interval. We have previously shown that wild type (WT) mice with high-fat diet induced obesity (DIO) have long QT and increased ventricular ectopy, mimicking the abnormalities found in obese humans. Our preliminary data now show that a high saturated fat diet is sufficient to cause ventricular ectopy and prolong the QT interval, and to promote inducibility of VT/VF. Further, mice fed a diet with an equivalent amount of monounsaturated fat from olive oil do not have heart rhythm abnormalities. We discovered that a high saturated fat diet increases cardiac NAPDH oxidase 2 (NOX2) activity, whereas the olive oil high-fat diet does not. The NOX2 inhibitor apocynin, when given during a high saturated fat diet, prevents heart rhythm abnormalities. Additional experiments with isolated cardiac myocytes show that NOX2 is necessary for the oxidative stress and mitochondrial dysfunction caused by saturated fat. We will use both in vivo experiments and cardiomyocytes to determine the pathways linking cardiac lipid metabolism to arrhythmia. Our central hypothesis is that NOX2 activation causes the arrhythmogenic effect of saturated fat by causing sarcoplasmic reticulum calcium leak, which in turn promotes mitochondrial dysfunction. We propose the following independent aims: 1. Determine if NOX2 activation causes arrhythmia during high fat diet, by using genetic gain and loss. 2. Determine how TLR4 signaling contributes to the arrhythmogenic effects of dietary saturated fat. 3. Determine if the mitochondrial abnormalities caused by NOX2 activation promote arrhythmia.

肥胖患者患心律失常的风险增加，是心脏猝死的风险的两倍，这是通常是由心室心动过速（VT）引起的。肥胖患者的心肌细胞增加了脂质含量，被认为有助于心律不齐的病理生理学。此外，较高的水平饮食中的血清脂肪酸和较高的饱和脂肪摄入预测心脏死亡。这表明这一点饱和脂肪的心律失常会发生，而无需肥胖。一个未解决的问题是：什么是在肥胖和高脂饮食期间引起心律不齐的分子机制？肥胖患者发现的最常见的电生理异常是 QT间隔的心室术和延长。我们以前已经证明了带有的野生型（WT）小鼠高脂饮食诱导的肥胖症（DIO）的QT很长，心室均增加，模仿异常在肥胖人类中发现。我们的初步数据现在表明，高饱和脂肪饮食足以引起心室eCectopy并延长QT间隔，并促进VT/VF的诱导性。此外，小鼠饮食来自橄榄油的同等含量脂肪的含量不具有心律异常。我们发现高饱和脂肪饮食增加了心脏NAPDH氧化酶2（NOX2）活性，而橄榄油高脂饮食没有。 NOX2抑制剂apocynin，在高饱和脂肪饮食期间给予防止心律异常。孤立心肌细胞的其他实验表明NOX2是对于由饱和脂肪引起的氧化应激和线粒体功能障碍所必需的。我们将两者都在体内实验和心肌细胞，以确定将心脏脂质代谢联系起来的途径心律不齐。我们的中心假设是NOX2激活会引起饱和脂肪的心律失常通过引起肌质网钙泄漏，进而促进线粒体功能障碍。我们提出以下独立目标： 1。通过使用遗传增益和损失，确定NOX2激活在高脂肪饮食期间是否引起心律不齐。 2。确定TLR4信号如何有助于饮食饱和脂肪的心律失常作用。 3。确定由NOX2激活引起的线粒体异常是否促进心律不齐。

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Mechanisms of Chronic Metabolic Stress in Arrhythmias.

DOI：
10.3390/antiox9101012
发表时间：
2020-10-19
期刊：
Antioxidants (Basel, Switzerland)
影响因子：
0
作者：
Gowen BH;Reyes MV;Joseph LC;Morrow JP
通讯作者：
Morrow JP

Sigma non-opioid receptor 1 is a potential therapeutic target for long QT syndrome.

DOI：
10.1038/s44161-021-00016-2
发表时间：
2022-03
期刊：
NATURE CARDIOVASCULAR RESEARCH
影响因子：
0
作者：
Song, LouJin;Bekdash, Ramsey;Morikawa, Kumi;Quejada, Jose R;Klein, Alison D;Aina-Badejo, Danielle;Yoshida, Kazushige;Yamamoto, Hannah E;Chalan, Amy;Yang, Risako;Patel, Achchhe;Sirabella, Dario;Lee, Teresa M;Joseph, Leroy C;Kawano, Fuun;Warren, Junco S;Soni, Rajesh K;Morrow, John P;Yazawa, Masayuki
通讯作者：
Yazawa, Masayuki

Paracardial fat and vitamin A: a mechanism for regulating exercise performance.

心旁脂肪和维生素 A：调节运动表现的机制。

DOI：
10.1172/jci145969
发表时间：
2021
期刊：
The Journal of clinical investigation
影响因子：
0
作者：
Joseph,LeroyC;Morrow,JohnP
通讯作者：
Morrow,JohnP

Combined metabolomic and transcriptomic profiling approaches reveal the cardiac response to high-fat diet.

DOI：
10.1016/j.isci.2022.104184
发表时间：
2022-05-20
期刊：
ISCIENCE
影响因子：
5.8
作者：
Joseph, Leroy C.;Shi, Jianting;Nguyen, Quynh N.;Pensiero, Victoria;Goulbourne, Chris;Bauer, Robert C.;Zhang, Hanrui;Morrow, John P.
通讯作者：
Morrow, John P.

Metformin Is Associated With a Lower Risk of Atrial Fibrillation and Ventricular Arrhythmias Compared With Sulfonylureas: An Observational Study.